The study of the interface pathogen-immune system is a relatively new area of intense research. Pathogens with the ability to establish a chronic or persistent infection have evolved sophisticated mechanisms to evade and/or modulate the immune response of their hosts. To this selected group of microorganisms belongs Brucella, a gram-negative, facultative intracellular bacteria that infects a broad range of mammals including humans and is one of the most distributed zoonosis in the world. Brucella abortus, the causative agent of bovine brucellosis, is still a major animal health problem in several countries and inflicts severe economical losses in endemic areas. Additionally, because of its capacity to induce a chronic and debilitating disease in humans and due to the lack of preventive and therapeutic therapies, it is classified as a warfare agent. Brucella, if not properly treated during the initial phases of the disease, establishes a chronic infection and is extremely hard to eliminate. To do so, Brucella has evolved a battery of immune evasion mechanisms that are able to tip the immune response to its own advantage but with minor alterations to the host homeostasis. This fine-tuned modulation is an exquisite example of the evolutionary result of a long-standing interaction between this pathogen and its host. The present application aims at studying two novel immune evasion strategies that we have identified in Brucella abortus. These two mechanisms target two different arms of the immune system: B-lymphocytes of the adaptive immune response and Toll-like receptor signaling in dendritic cells, a central component of the innate immune response. In the first case we propose to further study a polyclonal B-lymphocyte mitogen involved in the splenocyte anergy induced by Brucella during the acute phase of the infection. In the second case, the proposal aims at understanding in detail the function and mode of action of a new group of bacterial proteins with domains homologous to the Tir domains of the Toll-like receptor proteins that are able to interfere and/or modulate the outcome of the innate immune response. The present project will contribute to shed light on certain aspects of the molecular bases underlying the intricate host-pathogen interaction. PUBLIC HEALTH RELEVANCE: The bacterium Brucella causes a serious debilitating disease in animals and humans across the world. Our study will shed light on the mechanisms used by this pathogen to evade the immune response, opening the way for the development of new therapeutic agents.